We hypothesize that mutations in the Glucocerebrosidase gene and other lysosomal genes in the same biochemical pathway including Hexosaminidase A (HEXA), Sphingomyelin phosphodiesterase 1 (SMPD1) and mucolipin 1 (MCOLN1) may disrupt the cellular processing and trafficking of a-Synuclein and lead to Lewy Body formation. In our previous study, R21, NS050487, we have shown that mutations in the glucocerebrosidase gene are risk factors for PD and Lewy body disease. In the current application we propose to continue our studies on the GBA gene and will examine three additional lysosomal genes, mutations in which cause lysosomal storage disorders, namely, HEXA (Tay Sachs), SMPD1 (Niemann Pick Type A and B) and MCOLN1 (Mucolipidosis type IV) in clinically characterized PD patients and controls and LBD brain bank samples. There are two specific aims. In Aim1 we will identify genetic variation in 4 lysosomal including GBA, HEXA, SMPD1 and MCOLN1. First, for initial gene analysis, we will use a discovery set from the NY Ashkenazi Jewish study consisting of 300 cases and 300 controls (NY AJ, NS50487). We have chosen Ashkenazi Jewish cases and controls as a discovery set because it is a genetically homogeneous population and is likely to be more powerful than other admixed populations. Second, We will use a replication set from GEPD NS36630 and CORE PD NS36630 that comprises 1504 cases and 314 controls which will be used to examine allelic association of variants identified in the discovery set. Third, for alleles that are significant in the replication set we will combine the discovery and replication sets to estimate risk. The goal of Aim 2 is to further characterize Lewy Body brain autopsy samples. First, we will identify additional mutation carriers in additional Lewy body cases that are available in the NYBB. Second, We will measure enzyme activity (GBA, HEXA, SMPD1) or mRNA levels in addition to sphingolipid accumulation in neuropathologically defined Lewy body cases with lysosomal gene mutations compared to Lewy body cases without mutations and controls. Second, neuropathological evaluation of Lewy body brain autopsy samples with and without mutations will include quantitative and qualitative evaluation of a-synuclein positive structures in cortex, SN, hippocampus and cerebellum. PUBLIC HEALTH RELEVANCE: Significantly, recent studies suggest that mutations in lysosomal genes may be associated with PD and the lysosomal/autophagic pathway has also been implicated in PD pathogenesis. This study will serve to clarify the role of lysosomal genes in genetic susceptibility to PD.